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Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Identifieur interne : 000D15 ( Main/Exploration ); précédent : 000D14; suivant : 000D16

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Auteurs : Thomas S. Lisse ; Leah J. Middleton ; Adriana D. Pellegrini ; Paige B. Martin ; Emily L. Spaulding ; Olivia Lopes ; Elizabeth A. Brochu ; Erin V. Carter ; Ashley Waldron ; Sandra Rieger

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2016.

RBID : PMC:4839466

Abstract

Significance

Paclitaxel is a widely used chemotherapeutic agent in the treatment of cancer. Although paclitaxel arrests tumor growth through stabilizing microtubules, it also causes variable peripheral neuropathy in patients. A lack of understanding of the underlying mechanisms hinders therapeutic discovery, and commonly used mammalian models have not provided conclusive evidence about the etiology of this condition. To overcome this, we developed a larval zebrafish model that permits the analysis of paclitaxel neurotoxicity in living animals. This study identifies that keratinocyte damage and ectopic expression of matrix-metalloproteinase 13 (MMP-13) contributes to paclitaxel-induced peripheral neuropathy in zebrafish. We further show that inhibition of MMP-13 improves skin defects and prevents paclitaxel neurotoxicity. Thus, this study offers a previously unidentified avenue for potential therapeutic interventions.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839466

DOI: 10.1073/pnas.1525096113
PubMed: 27035978
PubMed Central: 4839466

Affiliations:

Le document en format XML

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 04672</nlm:aff>
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, Salisbury Cove,<addr-line>ME</addr-line>
 04672</nlm:aff>
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, Salisbury Cove,<addr-line>ME</addr-line>
 04672</nlm:aff>
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, Salisbury Cove,<addr-line>ME</addr-line>
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<front><div type="abstract" xml:lang="en"><title>Significance</title>
<p>Paclitaxel is a widely used chemotherapeutic agent in the treatment of cancer. Although paclitaxel arrests tumor growth through stabilizing microtubules, it also causes variable peripheral neuropathy in patients. A lack of understanding of the underlying mechanisms hinders therapeutic discovery, and commonly used mammalian models have not provided conclusive evidence about the etiology of this condition. To overcome this, we developed a larval zebrafish model that permits the analysis of paclitaxel neurotoxicity in living animals. This study identifies that keratinocyte damage and ectopic expression of matrix-metalloproteinase 13 (MMP-13) contributes to paclitaxel-induced peripheral neuropathy in zebrafish. We further show that inhibition of MMP-13 improves skin defects and prevents paclitaxel neurotoxicity. Thus, this study offers a previously unidentified avenue for potential therapeutic interventions.</p>
</div>
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<affiliations><list></list>
<tree><noCountry><name sortKey="Brochu, Elizabeth A" sort="Brochu, Elizabeth A" uniqKey="Brochu E" first="Elizabeth A." last="Brochu">Elizabeth A. Brochu</name>
<name sortKey="Carter, Erin V" sort="Carter, Erin V" uniqKey="Carter E" first="Erin V." last="Carter">Erin V. Carter</name>
<name sortKey="Lisse, Thomas S" sort="Lisse, Thomas S" uniqKey="Lisse T" first="Thomas S." last="Lisse">Thomas S. Lisse</name>
<name sortKey="Lopes, Olivia" sort="Lopes, Olivia" uniqKey="Lopes O" first="Olivia" last="Lopes">Olivia Lopes</name>
<name sortKey="Martin, Paige B" sort="Martin, Paige B" uniqKey="Martin P" first="Paige B." last="Martin">Paige B. Martin</name>
<name sortKey="Middleton, Leah J" sort="Middleton, Leah J" uniqKey="Middleton L" first="Leah J." last="Middleton">Leah J. Middleton</name>
<name sortKey="Pellegrini, Adriana D" sort="Pellegrini, Adriana D" uniqKey="Pellegrini A" first="Adriana D." last="Pellegrini">Adriana D. Pellegrini</name>
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Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish

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Abstract

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